SOX4 Is Essential for Prostate Tumorigenesis Initiated by PTEN Ablation
Birdal BilirAdeboye O. OsunkoyaW. Guy WilesSoma SannigrahiVéronique LefebvreDaniel MetzgerDemetri D. SpyropoulosWilliam MartinCarlos S. Moreno
74
Citation
41
Reference
10
Related Paper
Citation Trend
Abstract:
Abstract Understanding remains incomplete of the mechanisms underlying initiation and progression of prostate cancer, the most commonly diagnosed cancer in American men. The transcription factor SOX4 is overexpressed in many human cancers, including prostate cancer, suggesting it may participate in prostate tumorigenesis. In this study, we investigated this possibility by genetically deleting Sox4 in a mouse model of prostate cancer initiated by loss of the tumor suppressor Pten. We found that specific homozygous deletion of Sox4 in the adult prostate epithelium strongly inhibited tumor progression initiated by homozygous loss of Pten. Mechanistically, Sox4 ablation reduced activation of AKT and β-catenin, leading to an attenuated invasive phenotype. Furthermore, SOX4 expression was induced by Pten loss as a result of the activation of PI3K–AKT–mTOR signaling, suggesting a positive feedback loop between SOX4 and PI3K–AKT–mTOR activity. Collectively, our findings establish that SOX4 is a critical component of the PTEN/PI3K/AKT pathway in prostate cancer, with potential implications for combination-targeted therapies against both primary and advanced prostate cancers. Cancer Res; 76(5); 1112–21. ©2015 AACR.목적: PTEN은 염색체 10번에 위치하고 종양억제 유전자의 기능을 한다. 이러한 PTEN의 변형은 종양이 성장과 전이를 하기 위한 필수 과정인 신생혈관 형성을 촉진한다. 이에 우리나라에서 흔한 암종의 하나인 위암에서 PTEN의 발현을 평가하고, 생존율을 포함하는 여러 임상병리 인자 및 신생혈관 형성의 관련성에 대해 알아보고자 하였다. 대상 및 방법: 1993년 1월부터 1994년 12월까지 위암으로 진단을 받고, 수술을 시행하였던 90예를 대상으로 하였다. 위암조직에서 PTEN과 VEGF의 발현은 면역조직화학염색을 시행하여 염색의 강도와 범위에 따라 발현정도를 평가하였다. 결과: 대상군에서 PTEN 발현에 음성을 나타낸 예가 36예(40.0%), VEGF 발현에 양성인 경우가 70예(77.8%)였다. 그러나 PTEN 및 VEGF 발현은 생존율을 포함하는 여러 임상병리 인자들과 유의한 상관관계를 보이지 않았고 PTEN과 VEGF 발현 사이에 유의한 상관관계는 없었다. PTEN 발현에 따른 평균 미세혈관 수는 음성군이 90.4±43.0, 양성군이 73.6±28.3으로 음성군에서 양성군보다 유의하게 높았다(p=0.028). VEGF 발현에 따른 평균 미세혈관 수는 양성군이 86.4±36.7, 음성군이 59.0±21.3으로 양성군에서 음성군보다 유의하게 높았다(p=0.002). 또한, PTEN 발현이 음성이면서 VEGF 발현이 양성인 예의 평균 미세혈관 수는 98.0±42.2로 그 이외의 예보다 유의하게 높았다(p=0.001). 신생혈관 형성 정도와 생존율을 포함하는 여러 임상병리 인자의 관련성은 고신생혈관군에서 저신생혈관군보다 림프절 전이가 많았고, 생존율이 낮았다(p=0.014, 0.011). 결론: PTEN 발현소실은 신생혈관 형성 촉진을 통해 위암의 성장과 전이에 중요한 역할을 할 것으로 생각한다.
Cite
Citations (0)
We analyzed the levels of selected micro-RNAs in normal prostate tissue to assess their potential to indicate tumor foci elsewhere in the prostate. Histologically normal prostate tissue samples from 31 prostate cancer patients and two cancer negative control groups with either unsuspicious or elevated prostate specific antigen (PSA) levels (14 and 17 individuals, respectively) were analyzed. Based on the expression analysis of 157 microRNAs in a pool of prostate tissue samples and information from data bases/literature, we selected eight microRNAs for quantification by real-time polymerase chain reactions (RT-PCRs). Selected miRNAs were analyzed in histologically tumor-free biopsy samples from patients and healthy controls. We identified seven microRNAs (miR-124a, miR-146a & b, miR-185, miR-16 and let-7a & b), which displayed significant differential expression in normal prostate tissue from men with prostate cancer compared to both cancer negative control groups. Four microRNAs (miR-185, miR-16 and let-7a and let-7b) remained to significantly discriminate normal tissues from prostate cancer patients from those of the cancer negative control group with elevated PSA levels. The transcript levels of these microRNAs were highly indicative for the presence of cancer in the prostates, independently of the PSA level. Our results suggest a microRNA-pattern in histologically normal prostate tissue, indicating prostate cancer elsewhere in the organ.
Prostate biopsy
Cite
Citations (17)
Tensin
Cite
Citations (255)
目的将与 anti-oncogene PTEN 研究同类和 PTEN 的贡献到胃的癌和关系的致癌作用和发展。方法同类和 PTEN 蛋白质，正常的 76 格的 PTEN mRNA 胃有粘液并且胃的癌的 112 格被免疫组织化学检测方法和原位杂交。同类，在胃的癌组的 PTEN 蛋白质和正常胃粘膜的表示组织的结果，肌层侵略的组，淋巴的转移组和非淋巴的转移组织的侵略的组和没有肌层都是统计意义(P < 0.05 或 P< 0.01 ) 。胃的癌组的 PTEN mRNA 的表示比正常胃粘膜组的低(P < 0.01 ) 。同类和 PTEN 蛋白质的表示有否定关联(r =−0.347， P < 0.01 ) 。增加的结论同类蛋白质和减少的 PTEN 蛋白质仔细与胃的癌的开始和发展有关系，并且控制他们可以成为一个新对待目标胃的癌症。
Cite
Citations (0)
To evaluate the spatial distribution of prostate cancer detected at a single positive biopsy (PBx) and a repeat PBx (rPBx).We evaluated 533 consecutive men diagnosed with prostate cancer who underwent radical prostatectomy using a clinical map document based on XML (cMDX©)-based map model of the prostate. We determined the number of cancer foci, relative tumour volume, Gleason score, zone of origin, localisation, and pathological stage after stratification according to the number of PBx sessions (PBx vs rPBx). The distribution of 3966 prostate cancer foci was analysed and visualised on heat maps. The colour gradient of the heat map was reduced to six colours representing the frequency classification of prostate cancer using an image posterisation effect. Additionally, the spatial distribution of organ-confined prostate cancer between PBx and rPBx was evaluated.Prostate cancer diagnosed on PBx was mostly localised to the apical portion and the peripheral zone of the prostate. Prostate cancer diagnosed on rPBx was more frequently found in the anterior portion and the base of the prostate. Organ-confined prostate cancer foci were mostly localised in the dorsolateral zone of the prostate in men at PBx, whereas men at rPBx had more prostate cancer foci in the anterior portion.The spatial distribution of prostate cancer with rPBx differs significantly from the spatial distribution of prostate cancer with PBx. The whole anterior portion of the prostate should be considered by rPBx.
Cite
Citations (7)
Tensin
Cite
Citations (27)
Objective To investigate the expressions of mitosis regulative factor STK-15 in prostate cancer and the relationship between STK-15 and the biological behavior of prostate cancer.Methods The expressions of STK-15 were examined by using immunohistochemical staining on 63 cases of prostate cancer and 16 cases of normal prostate tissues.And the expressions of STK-15 mRNA were detected by using RT-PCR in 14 cases of prostate cancer,BPH,and normal prostate tissues respectively.Results The STK15 protein was expressed in 98%(62/63) of prostate cancer tissue and in 19%(3/16) of normal prostate tissues.The difference between these expression rates was significant(P0.001).Meanwhile,the positive expression rates of STK-15 mRNA in prostate cancer,BPH,and normal prostate tissue were 93%(13/14),21%(3/14) and 14%(2/14) respectively.Compared with those in BPH and normal prostate tissue,the STK-15 mRNA expression rate in prostate cancer was significantly high(P0.001).Meanwhile,there was no significant difference between those in BPH and normal prostate tissue(P0.05).Conclusion The expressions of STK-15 increase in prostate cancer tissues which may contribute to the prostate carcinogenesis.
Prostate Diseases
Cite
Citations (0)
Σκοπός της μελέτης: H απώλεια του PTEN και οι μεταλλάξεις του PIK3CA έχουν μελετηθεί ως δείκτες ενεργοποίησης του σηματοδοτικού μονοπατιού PI3K στον καρκίνο του μαστού. Αξιολογήσαμε αυτούς τους δείκτες σε πρώιμο καρκίνο του μαστού (EBC) υψηλού κινδύνου για υποτροπή, επικεντρώνοντας σε θέματα ανοσοϊστοχημείας (IHC) του PTEN, ιδιαίτερα στη HER2 θετική νόσο. Υλικά και μέθοδοι: Εξετάσαμε την απώλεια του PTΕΝ και τις μεταλλάξεις του PIK3CA σε 1265 ασθενείς με EBC που έλαβαν συμπληρωματική χημειοθεραπεία σε δύο κλινικές δοκιμές. Χρησιμοποιήθηκαν δύο διαφορετικές μέθοδοι για την αξιολόγηση της ανοσοϊστοχημικής έκφρασης του PTEN, μία εκ των προτέρων δυαδική (απώλεια, μη απώλεια) και η άλλη αρχικά πολλαπλών κλιμάκων που επέτρεπε την ταξινόμηση όγκων "γκρίζας ζώνης" με χαμηλή και πολύ χαμηλή έκφραση πρωτεϊνών PTEN. Αποτελέσματα: Η απώλεια PTEN (33,4% και 22,1%, ανάλογα με τη μέθοδο IHC) και οι μεταλλάξεις PIK3CA (29,6%) συσχετίστηκαν με ER / PR / HER2-αρνητική και ER / PR θετική ασθένεια αντίστοιχα. Η συμφωνία των δύο μεθόδων IHC ήταν μέτρια (Cohen's kappa 0.624). Η ασυμφωνία στην εκτίμηση της απώλειας PTEN και η ετερογένεια εντός του όγκου αφορούσαν όγκους "γκρίζας ζώνης" και επικρατούσαν στους HER2-θετικούς καρκίνους. Η απώλεια του PTEN συσχετίστηκε με αυξημένο κίνδυνο για υποτροπή και θάνατο. Σε σύγκριση με τις μεμονωμένες μεταλλάξεις PIK3CA, η απλή απώλεια PTEN συνδέθηκε ανεξάρτητα με αυξημένο κίνδυνο υποτροπής και θανάτου. Ανάλογα με τη μέθοδο αξιολόγησης, σε HER2-θετικό καρκίνο, η απώλεια PTEN ήταν χωρίς ή με οριακή αρνητική προγνωστική σημασία. Συμπέρασμα: Στον EBC, η απώλεια PTEN είναι ένας ανεξάρτητος αρνητικός προγνωστικός δείκτης για την κλινική έκβαση των ασθενών. Όταν εμφανίζονται μεμονωμένα, η απώλεια PTEN και οι μεταλλάξεις PIK3CA έχουν αντίθετη προγνωστική επίδραση. Σε HER2 θετική νόσο, η εκτίμηση της απώλειας PTEN από την IHC φαίνεται αναξιόπιστη και ο δείκτης δεν έχει σαφή προγνωστική σημασία.
Cite
Citations (0)
Abstract Background We assessed the effect of biopsy location on the prostate cancer detection and clinically significant prostate cancer. Methods A total of 2774 patients with 12‐core prostate transrectal ultrasound‐guided prostate biopsy were included for per core analysis. Multivariate Cox regression analysis was performed to evaluate the effect of the location of biopsy on the prostate cancer and clinically significant prostate cancer detection. Results Prostate cancer was found in 775 patients (27.9%) and 576 prostate cancer patients (20.8%) were found to be clinically significant. The core length ( P = .043), tumor length ( P < .001), and % tumor length ( P < .001) were significantly different according to the biopsy location. The detection rates for prostate cancer and clinically significant prostate cancer differed significantly according to the location of biopsy. Multivariate analysis revealed that the apical core was significantly related with increased detection of prostate cancer and clinically significant prostate cancer. The lateral core, in addition to apical core, was found to be significantly related with increased detection rates of prostate cancer and clinically significant prostate cancer in men with prostate‐specific antigen <10 ng/mL. Conclusions More in‐depth discussions on the location of standard 12‐core prostate biopsy are considered necessary. Apical core and lateral core biopsies may be helpful, especially in patients with prostate‐specific antigen ˂10 ng/mL if additional biopsies are planned following findings of no target lesions on imaging studies.
Prostate biopsy
Cite
Citations (0)